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Amine promiscuity and toxicology analysis.

Esther C Y Lee1, Gregory Steeno2, Anne Mai Wassermann3

  • 1Medicine Design, Pfizer Worldwide Research & Development, Cambridge, MA 02139, United States.

Bioorganic & Medicinal Chemistry Letters
|December 25, 2016
PubMed
Summary

Primary amines offer a promising solution for drug discovery, leading to longer drug half-lives and reduced off-target toxicity. This study found primary amines to be less promiscuous than secondary and tertiary amines.

Keywords:
AminesHalf-lifePharmacological profilingPromiscuityToxicology

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Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Drug Discovery

Background:

  • Achieving a sufficient duration of drug action, indicated by longer half-lives, is a key challenge in drug discovery.
  • Drug half-life is influenced by the volume of distribution, which can depend on a molecule's ionization state.
  • Basic compounds often exhibit higher volumes of distribution, potentially leading to extended half-lives, but may also increase promiscuity.

Purpose of the Study:

  • To investigate the role of primary, secondary, and tertiary amines in drug promiscuity and off-target toxicity.
  • To analyze in vitro pharmacological profiling and toxicology data to understand amine behavior.

Main Methods:

  • Analysis of in vitro pharmacological profiling data.
  • Evaluation of in vivo toxicology study results.
  • Comparison of promiscuity and toxicity profiles across different amine types (primary, secondary, tertiary).

Main Results:

  • Primary amines demonstrated lower promiscuity in in vitro assays.
  • Secondary and tertiary amines showed higher promiscuity.
  • Primary amines exhibited improved profiles in in vivo toxicology studies compared to secondary and tertiary amines.

Conclusions:

  • Primary amines represent a favorable chemical moiety for drug development, balancing extended duration of action with reduced off-target toxicity.
  • Minimizing the use of secondary and tertiary amines may help mitigate promiscuity-associated toxicity in drug candidates.